Metabolism

The Cellular Benefits of Exercise

It has been said that if exercise were a pill, it would be the most widely prescribed medicine in the world. Its benefits, especially in relation to diabetes, are undisputed. Regular physical activity reduces the risk of developing type 2 diabetes; it also helps people with type 1 or type 2 diabetes better control their blood glucose and avoid long-term complications like heart disease. The challenge to scientists, however, is to find out how physical activity exerts these beneficial effects on the molecular and cellular levels.

Researchers in the Section on Metabolism are recognized internationally for advancing the scientific understanding of exercise physiology and biochemistry, conducting the most comprehensive studies to understand how exercise works to regulate metabolism in muscle. Although researchers focus on learning how physical activity enhances insulin sensitivity and improves glucose metabolism—two important issues in diabetes—their studies also provide insight into other chronic and life-threatening conditions, such as obesity and heart disease.

Activity’s Alternate Pathways

Glucose circulating in the blood can nourish the body only if it can enter individual cells, which then convert it to energy. Key players in this process are glucose transporters, molecules that must travel from inside the cell to its membrane to ferry glucose into the cell.

However, proteins that are part of the complex signaling pathways in the cell must be activated before these glucose transporters can move to the membrane. In people with diabetes, the insulin-signaling pathway is damaged, thereby causing the glucose transporters to lag inside the starving cell as much-needed glucose circulates outside.

In a significant breakthrough several years ago, researchers in the section showed that exercise is beneficial because it activates alternate signaling pathways that appear to be just as potent in moving glucose into a cell as the insulin-signaling pathway. Building on this research, they identified a key molecule that acts as a “fuel gauge” in at least one “exercise-signaling pathway” and possibly more.

The fuel gauge is adenosine monophosphate-activated protein (AMP) kinase, an enzyme that is stimulated when muscles contract. Section investigators showed that during exercise, AMP kinase activity increases so that more glucose enters and energizes muscle cells.

In follow-up studies, researchers demonstrated that the blood glucose-lowering drug metformin exerts its effects, in part, by targeting AMP kinase. In addition, they discovered that AMP kinase is not the only protein that can work as an insulin-independent regulator of glucose transport into cells. Now investigators are working with pharmacologists to develop drugs that target AMP kinase and other proteins specifically—and perhaps provide even better blood glucose control.

A Broader Health Focus

Understanding why exercise is good for overall health is another major focus in the section. Thus investigators study signaling proteins activated by exercise and how they interact with other proteins to achieve muscle resilience, endurance and overall health.

Follow-up studies of AMP kinase and AMP kinase-related proteins have shown that these proteins are important not only during acute bouts of exercise, but also during endurance training. These studies found that AMP kinase alters muscle fuel reserves and affects the activity of other exercise-responsive genes to make muscles more adaptive and resilient.

The section is planning future studies to determine precisely how all these genes interact to improve overall health. Metabolism section scientists are also beginning to study the role of these genes in fat cell and liver metabolism, tissues that also respond to exercise, and are likely to be fundamental players in the health benefits of regular physical activity. Researchers will tackle these challenges by using genetically-engineered animal models to study the function of genes in vivo.

In a technological breakthrough, investigators developed a way to conduct transfection studies of the genes in animals. (Transfection is a technique in which scientists introduce a particular gene only in a particular type of cell.) Although other institutions have conducted transfection studies in cell cultures, Joslin investigators have been the first to routinely express proteins into the skeletal muscles of a living animal.